Before European settlement the region was inhabited by Cheraw Indians. Welsh Baptists from Delaware were granted land along the Great Pee Dee in 1737. Marlboro county was established in 1785 and named for John Churchill, 1st duke of Marlborough. In 1865, during the American Civil War, it was ravaged by Union troops led by Gen. William Tecumseh Sherman.

Throughout the 19th and 20th centuries Marlboro county was a leading producer of cotton; soybeans, tobacco, and grains are other major crops. The manufacture of textile products is also important. Bennettsville is the county seat. Area 480 square miles (1,242 square km). Pop. (2000) 28,820; (2010) 28,933.